Aqueous iron carbohydrate complexes, their production and medicaments containing them

ABSTRACT

A water soluble iron carbohydrate complex obtainable from an aqueous solution of iron(III) salt and an aqueous solution of the oxidation product of one or more maltrodextrins using an aqueous hypochlorite solution at a pH-value within the alkaline range, where, when one maltodextrin is applied, its dextrose equivalent lies between 5 and 20, and when a mixture of several maltodextrins is applied, the dextrose equivalent of the mixture lies between 5 and 20 and the dextrose equivalent of each individual maltodextrin contained in the mixture lies between 2 and 40, a process for its production and a medicament for the treatment and prophylaxis of iron deficiency conditions.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/581,212, filed Oct. 19, 2009, which is incorporated by reference inits entirety herein and which is a division of U.S. application Ser. No.10/531,895, filed Dec. 14, 2005, which issued as U.S. Pat. No. 7,612,109on Nov. 3, 2009 and which is a national stage application under 35U.S.C. §371 of PCT/EP2003/011596, filed Oct. 20, 2003, which claimsbenefit of German application 102 49 552.1, filed Oct. 23, 2002.

BACKGROUND OF THE INVENTION

Iron deficiency anemia can be treated or prophylactically treated by theapplication of medicaments containing iron. In this respect the use ofiron carbohydrate complexes is known. A water soluble iron (III)hydroxide sucrose complex is a frequently and successfully usedpreparation (Danielson, Salmonson, Derendorf, Geisser, Drug Res., Vol.46: 615-621, 1996). It is also known in the art to use, for parenteralapplication, iron dextran complexes as well as complexes based onpullulans (WO 02/46241), which are difficult to obtain and have to beproduced under pressure at high temperatures and involving hydrogenatingsteps. Other iron carbohydrate complexes are also known for oralapplication.

BRIEF SUMMARY OF THE INVENTION

The present invention concerns water-soluble iron carbohydrate complexeswhich are used for the treatment of iron deficiency anemia, theirpreparation, medicaments containing them and their use for theprophylaxis or treatment of iron deficiency anemia. The medicaments areespecially useful for parenteral application.

DETAILED DESCRIPTION OF THE INVENTION

The problem to be solved by the present invention is to provide an ironpreparation which is especially to be applied parenterally and which caneasily be sterilized; the known parenterally applicable preparations onthe basis of sucrose and dextran were only stable at temperatures up to100° C., which made sterilization difficult. Further, the preparation tobe provided by the invention shall have reduced toxicity and shall avoiddangerous anaphylactic shocks which can be induced by dextran. Also, thestability of the complexes of the preparation shall be high in order toenable a high applicable dosage and a high rate of application.Furthermore, the iron preparation is to be producible from easilyobtainable starting products and without great effort.

In accordance with the present invention the problem can be solved byproviding iron (III) carbohydrate complexes on the basis of theoxidation products of maltodextrins. Therefore, an object of the presentinvention is water soluble iron carbohydrate complexes, which areobtainable from an aqueous solution of an iron (III) salt and an aqueoussolution of the oxidation product of one or more maltodextrins, using anaqueous hypochlorite solution at an alkaline pH value, e.g., of 8 to 12where, when one maltodextrin is applied, its dextrose equivalent liesbetween 5 and 20, and when a mixture of several maltodextrins isapplied, the dextrose equivalent of the mixture lies between 5 and 20and the dextrose equivalent of each individual maltodextrin contained inthe mixture lies between 2 and 40.

A further object of the present invention is a process for producing theiron carbohydrate complexes according to the invention wherein one ormore maltodextrins are oxidized in an aqueous solution at an alkaline pHvalue, e.g., of 8 to 12 using an aqueous hypochlorite solution andreacting the obtained solution with an aqueous solution of an iron (III)salt where, when one maltodextrin is applied, its dextrose equivalentlies between 5 and 20, and when a mixture of several maltodextrins isapplied, the dextrose equivalent of the mixture lies between 5 and 20and the dextrose equivalent of each individual maltodextrin contained inthe mixture lies between 2 and 40.

The usable maltodextrins are easily obtainable starting products, andthey are commercially available.

In order to prepare the ligands of the complexes of the invention, themaltodextrins are oxidized in an aqueous solution with a hypochloritesolution. Suitable examples are solutions of alkali hypochlorites suchas a solution of sodium hypochlorite. Commercially available solutionscan be used. The concentration of the hypochlorite solution, e.g., is atleast 13% by weight, preferably on the order of 13 to 16% by weight,calculated as active chlorine. Preferably the solutions are used in suchan amount that about 80 to 100%, preferably about 90%, of one aldehydegroup per molecule of maltodextrin is oxidized. In this manner, thereactivity caused by the glucose content of the maltodextrin moleculesis lowered to 20% or less, preferably to 10% or less.

The oxidation is carried out in an alkaline solution, e.g., at a pH of 8to 12, for example 9 to 11. As an example, oxidation can be carried outat temperatures on the order of 15 to 40° C., preferably of 25 to 35° C.The reaction times are, e.g, on the order of 10 minutes to 4 hours,e.g., 1 to 1.5 hours.

By this procedure the degree of depolymerization of the startingmaltodextrins is kept at a minimum. Only theoretically it is assumedthat the oxidation occurs mainly at the terminal aldehyde group (acetalor semiacetal group, respectively) of the maltodextrin molecules.

It is also possible to catalyze the oxidation reaction of themaltodextrins. The addition of bromide ions is suitable, e.g., in theform of alkali bromides, for example sodium bromide. The added amount ofbromide is not critical. The amount is kept as low as possible in orderto achieve an end product (Fe-complex) which can easily be purified.

Catalytic amounts are sufficient. As stated above, the addition ofbromide is possible, however, not necessary.

Further, it is also possible to use other oxidation systems, such as,e.g., the known ternary oxidation system hypochlorite/alkalibromide/2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) for the oxidationof the maltodextrins. The process to oxidize maltodextrins catalyticallywith alkali bromides or with the ternary TEMPO system is described,e.g., by Thaburet et al, in Carbohydrate Research 330 (2001) 21-29,which method can be used for the present invention,

In order to prepare the complexes of the invention, the obtainedoxidized maltodextrins are reacted with an iron (III) salt in an aqueoussolution. In order to do so, the oxidized maltodextrins can be isolatedand redissolved. It is also possible, however, to use the obtainedaqueous solutions of the oxidized maltodextrins directly for the furtherreaction with the aqueous iron (III) solutions.

Water soluble salts of inorganic or organic acids, or mixtures thereof,such as halides, e.g., chloride and bromide, or sulfates can be used asiron (III) salts. It is preferred to use physiologically acceptablesalts. It is especially preferred to use an aqueous solution of iron(III) chloride.

It has been found that the presence of chloride ions favors theformation of the complexes. The chloride ions can be used in the form ofwater soluble chlorides such as alkali metal chlorides, e.g., sodiumchloride, potassium chloride or ammonium chloride. As stated, the iron(III) is preferably used in the form of the chloride.

For instance, the aqueous solution of the oxidized maltodextrin can bemixed with an aqueous solution of the iron (III) salt in order to carryout the reaction. Here, it is preferred to proceed in a manner so thatduring and immediately after mixing the oxidized maltodextrin and theiron (III) salt, the pH is strongly acid or so low that no hydrolysis ofthe iron (III) salt occurs, e.g., pH 2 or less, in order to avoid anundesired precipitation of iron hydroxides. In general, it is notnecessary to add an acid, if iron (III) chloride is used, since aqueoussolutions of iron (III) chloride can be sufficiently acidic. Only aftermixing, the pH is raised to values, e.g., on the order of at least 5,for example, up to 11, 12, 13 or 14. The pH is preferably raised slowlyor gradually which, for example, can be achieved by first adding a weakbase, for example, up to a pH of about 3, and then neutralizing furtherusing a stronger base. Examples of weak bases are alkali—or alkalineearth—carbonates, bicarbonates, such as sodium and potassium carbonateor bicarbonate, or ammonia. Examples of strong bases are alkali—oralkaline earth—hydroxides such as sodium, potassium, calcium ormagnesium hydroxide.

The reaction can be improved by heating. For example, temperatures onthe order of 15° C. up to boiling point can be used. It is preferred toraise the temperature gradually. Thus, for example, it is possible toheat to about 15 to 70° C. and then raise the temperature gradually upto boiling point.

The reaction times are, for example, on the order of 15 minutes up toseveral hours, e.g., 20 minutes to 4 hours, such as 25 to 70 minutes,e.g., 30 to 60 minutes.

The reaction can be carried out in a weakly acid range, for example, ata pH on the order of 5 to 6. However, it has been found, that it isuseful, but not necessary, to raise the pH during the formation of thecomplexes to higher values of up to 11, 12, 13 or 14. In order tocomplete the reaction, the pH can be lowered then by addition of anacid, for example, to the order of 5 to 6. It is possible to useinorganic or organic acids or a mixture thereof, especially hydrogenhalide acids such as hydrogen chloride or aqueous hydrochloric acid,respectively.

As stated above, the formation of the complexes is usually improved byheating. Thus, at the preferred embodiment of the invention, wherein thepH is raised during the reaction to ranges of at least 5 and above, upto 11 or 14, it is, for instance, possible to work at first at lowertemperatures on the order of 15 to 70° C., such as 40 to 60° C., e.g.,about 50° C., whereafter the pH is reduced to values on the order of atleast 5, and the temperature is gradually raised over 50° C. up toboiling point

The reaction times are on the order of 15 minutes up to several hoursand they can vary depending on the reaction temperature. If the processis carried out with an intermediate pH of more than 5, it is, forexample, possible to work 15 to 70 minutes, e.g., 30 to 60 minutes, atthe enhanced pH, for example, at temperatures of up to 70° C.,whereafter the pH is lowered to a range on the order of at least 5 andthe reaction is carried out for a further 15 to 70 minutes, e.g., 30 to60 minutes, at temperatures, e.g., up to 70° C., and optionally afurther 15 to 70 minutes, e.g., 30 to 60 minutes, at higher temperaturesup to boiling point.

After the reaction the obtained solution can be cooled, e.g., to roomtemperature and can optionally be diluted and optionally be filtered.After cooling, the pH can be adjusted to the neutral point or a littlebelow, for example, to values of 5 to 7, by the addition of an acid orbase. It is possible to use, e.g., the acids and bases which have beenmentioned for carrying out the reaction. The solutions obtained arepurified and can directly be used for the production of medicaments.However, it is also possible to isolate the iron (III) complexes fromthe solution, e.g., by precipitation with an alcohol such as an alkanol,for example, ethanol. Isolation can also be effected by spray-drying.Purification can take place in the usual way, especially in order toremove salts. This can, for example, be carried out by reverse osmosis.It is, for example, possible to carry out the reverse osmosis beforespray-drying or before a direct application in medicaments.

The iron content of the obtained iron (III) carbohydrate complexes is,for example, 10 to 40% weight/weight, especially, 20 to 35%weight/weight. They can easily be dissolved in water. It is possible toprepare neutral aqueous solutions which, e.g., have an iron content of1% weight/vol. to 20% weight/vol. Such solutions can be sterilizedthermically. The weight average molecular weight of the obtainedcomplexes, is, for example, 80 kDa to 400 kDa, preferably 80 kDa to 350kDa, especially preferred up to 300 kDa (measured by gel permeationchromatography, e.g., as described by Geisser et al, in Arzneim.Forsch/Drug Res. 42(11), 12, 1439-1452 (1992), paragraph 2.2.5).

As stated above, it is possible to provide aqueous solutions from thecomplexes of the invention. These solutions are especially useful forparenteral application. However, it is also possible to apply themorally or topically. Contrary to the known parenterally applicable ironpreparations, they can be sterilized at high temperatures, e.g., at 121°C. and above, at short contact times of, e.g., 15 minutes, by acquiringF₀≧15. The contact times are correspondingly shorter at highertemperatures. Preparations hitherto known had to be sterilely filtratedand mixed with preservatives, such as benzyl alcohol or phenol. Suchadditives are not necessary in the invention. Hence, it is possible tofill the solutions of the complexes, for example, into ampoules. It is,for example, possible to fill solutions having a content of 1 to 20% byweight, e.g., 5% by weight, into vessels such as ampoules or phials,e.g., of 2 to 100 ml, e.g., up to 50 ml. The preparation of theparenterally applicable solutions can be carried out as known in theart, optionally using additives which are normally used for parenteralsolutions. The solutions can be formulated in such a way that they canbe administered by injection or in the form of an infusion, e.g., inbrine solution. For the oral or topical application it is possible toformulate preparations with usual excipients and additives.

Thus, a further object of the invention is aqueous medicaments which areespecially useful for the parenteral, intravenous but also intramuscularapplication, as well as for oral or topical application. The aqueousmedicaments are especially useful for the treatment of iron deficiencyanemia. A further object of the invention is also the use of the iron(III) carbohydrate complexes according to the invention for thetreatment and prophylaxis of iron deficiency anemia or the production ofmedicaments especially for the parenteral treatment of iron deficiencyanemia. The medicaments can be used in human and veterinary medicine.

The advantages which are achieved with the iron (III) carbohydratecomplexes of the invention are the above-mentioned high sterilizationtemperatures, as well as the low toxicity and the reduced danger ofanaphylactic shock. The toxicity of the complexes according to theinvention is very low. The LD₅₀ lies at over 2000 mg Fe/kg, compared tothe LD₅₀ of the known pullulan complexes, which lies at 1400 mg Fe/kg.In view of the high stability of the complexes of the invention, it ispossible to enhance the rates of application as well as the dosages.Thus, it is possible to apply the medicaments of the inventionparenterally in the form of a single dose. Such a single dose is, forexample, 500 to 1000 mg iron. The dose can be applied, for example,during the course of one hour. A further advantage lies in the highdegree of availability of the maltodextrins used as starting products,which are, e.g., commercially available additives in the food processingindustry.

In the present description, as well as in the following examples, thedextrose equivalents are measured gravimetrically. In order to do so,the maltodextrins are reacted in a boiling aqueous solution withFehling's solution. The reaction is carried out quantitatively, i.e.until the Fehling's solution is no longer discolored. The precipitatedcopper (I) oxide is dried at 105° C. until a constant weight is achievedand measured gravimetrically. The glucose content (dextrose equivalent)is calculated from the obtained results as % weight/weight of themaltodextrin dry substance. It is, for example, possible to use thefollowing solutions: 25 ml Fehling's solution I, mixed with 25 mlFehling's solution II; 10 ml aqueous maltodextrin solution (10% mol/vol)(Fehling's solution I: 34.6 g copper (II) sulfate dissolved in 500 mlwater; Fehling's solution II: 173 g potassium sodium tartrate and 50 gsodium hydroxide dissolved in 400 ml water).

Example 1

100 g maltodextrin (9.6 dextrose equivalent measured gravimetrically)are dissolved by stirring in 300 ml water at 25° C. and oxidized byaddition of 30 g sodium hypochlorite solution (13 to 16 weight percentactive chlorine) at pH 10.

At first, the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then, the pH is adjusted to 11 by addition of sodium hydroxide, and thesolution is heated to 50° C. and kept at 50° C. for 30 minutes. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 30 minutes and thenheated to 97-98° C., and the temperature is kept for 30 minutes at thisrange. After cooling the solution to room temperature, the pH isadjusted to 6-7 by the addition of sodium hydroxide.

The solution is then filtered through a sterilization filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85, and then dried invacuum at 50° C.

The yield is 125 g (corresponding to 87% of the theoretical value) of abrown amorphic powder having an iron content of 29.3% weight/weight(measured complexometrically).

Molecular weight mw 271 kDa.

Example 2

200 g maltodextrin (9.6 dextrose equivalent measured gravimetrically)are dissolved by stirring in 300 ml water at 25° C. and oxidized byaddition of 30 g sodium hypochlorite solution (13 to 16 weight percentactive chlorine) at pH 10.

At first, the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then, the pH is adjusted to 11 by addition of sodium hydroxide, and thesolution is heated to 50° C. and kept for 30 minutes at 50° C. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 30 minutes and thenheated to 97-98° C., and the temperature Is kept for 30 minutes at thisrange. After cooling the solution to room temperature, the pH isadjusted to 6-7 by the addition of sodium hydroxide.

The solution is then filtered through a sterilization filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85, and then dried invacuum at 50° C.

The yield is 123 g (corresponding to 65% of the theoretical value) of abrown amorphic powder having an iron content of 22.5% weight/weight(measured complexometrically).

Molecular weight mw 141 kDa,

Example 3

100 g maltodextrin (9.6 dextrose equivalent measured gravimetrically)are dissolved by stirring in 300 ml water at 25° C. and oxidized byaddition of 30 g sodium hypochlorite solution (13 to 16 weight percentactive chlorine) and 0.7 g sodium bromide at pH 10.

At first, the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then, the pH is adjusted to 6.5 by addition of sodium hydroxide and thesolution is heated to 50° C. and kept for 60 minutes at 50° C. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 30 minutes and thenheated to 97-98° C., and the temperature is kept for 30 minutes at thisrange. After cooling the solution to room temperature the pH is adjustedto 6-7 by the addition of sodium hydroxide.

The solution is then filtered through a sterilization filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85 and then dried in vacuumat 50° C.

The yield is 139 g. (corresponding to 88% of the theoretical value) of abrown amorphic powder having an iron content of 26.8% weight/weight(measured complexometrically).

Molecular weight mw 140 kDa.

Example 4

A mixture of 45 g maltodextrin (6.6 dextrose equivalent measuredgravimetrically) and 45 g maltodextrin (14.0 dextrose equivalentmeasured gravimetrically) is dissolved by stirring in 300 ml water at25° C. and oxidized by addition of 25 g sodium hypochlorite solution (13to 16 weight percent active chlorine) and 0.6 g sodium bromide at pH 10.

At first, the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then, the pH is adjusted to 11 by addition of sodium hydroxide and thesolution is heated to 50° C. and kept for 30 minutes at 50° C. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 30 minutes and thenheated to 97-98° C., and the temperature is kept for 30 minutes at thisrange. After cooling the solution to room temperature the pH is adjustedto 6-7 by the addition of sodium hydroxide.

The solution is then filtered through a sterilization filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85 and then dried in vacuumat 50° C.,

The yield is 143 g (corresponding to 90% of the theoretical value) of abrown amorphic powder having an iron content of 26.5% weight/weight(measured complexometrically).

Molecular weight mw 189 kDa,

Example 5

90 g maltodextrin (14.0 dextrose equivalent measured gravimetrically)are dissolved by stirring in 300 ml water at 25° C. and oxidized byaddition of 35 g sodium hypochlorite solution (13 to 16 weight percentactive chlorine) and 0.6 g sodium bromide at pH 10.

At first, the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then, the pH is adjusted to 11 by addition of sodium hydroxide and thesolution is heated to 50° C. and kept for 30 minutes at 50° C. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 30 minutes and thenheated to 97-98° C. and the temperature is kept for 30 minutes at thisrange. After cooling the solution to room temperature the pH is adjustedto 6-7 by the addition of sodium hydroxide.

The solution is then filtered through a sterilization filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85 and then dried in vacuumat 50° C.

The yield is 131 g (corresponding to 93% of the theoretical value) of abrown amorphic powder having an iron content of 29.9% weight/weight(measured complexometrically).

Molecular weight mw 118 kDa.

Example 6

A mixture of 45 g maltodextrin (5.4 dextrose equivalent measuredgravimetrically) and 45 g maltodextrin (18.1 dextrose equivalentmeasured gravimetrically) is dissolved by stirring in 300 ml water at25° C. and oxidized by addition of 31 g sodium hypochlorite solution (13to 16 weight percent active chlorine) and 0.7 g sodium bromide at pH 10.

At first, the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then, the pH is adjusted to 11 by addition of sodium hydroxide and thesolution is heated to 50° C. and kept for 30 minutes at 50° C. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 30 minutes and thenheated to 97-98° C. and the temperature is kept for 30 minutes at thisrange. After cooling the solution to room temperature the pH is adjustedto 6-7 by the addition of sodium hydroxide.

The solution is then filtered through a sterilization filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85 and then dried in vacuumat 50° C.

The yield is 134 g (corresponding to 88% of the theoretical value) of abrown amorphic powder having an iron content of 27.9% weight/weight(measured complexometrically).

Molecular weight mw 178 kDa.

Example 7

100 g maltodextrin (9.6 dextrose equivalent measured gravimetrically)are dissolved by stirring in 300 ml water at 25° C. and oxidized byaddition of 29 g sodium hypochlorite solution (13 to 16 weight percentactive chlorine) and 0.7 g sodium bromide at pH 10.

At first, the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then, the pH is adjusted to 11 by addition of sodium hydroxide and thesolution is heated to 50° C. and kept for 30 minutes at 50° C. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 70 minutes. Aftercooling the solution to room temperature the pH is adjusted to 6-7 bythe addition of sodium hydroxide.

The solution is then filtered through a sterilization filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85 and then dried in vacuumat 50° C.

The yield is 155 g (corresponding to 90% of the theoretical value) of abrown amorphic powder having an iron content of 24.5% weight/weight(measured complexometrically).

Molecular weight mw 137 kDa.

Example 8

126 g maltodextrin (6.6 dextrose equivalent measured gravimetrically)are dissolved by stirring in 300 ml water at 25° C. and oxidized byaddition of 24 g sodium hypochlorite solution. (13 to 16 weight percentactive chlorine) and 0.7 g sodium bromide at pH 10.

At first, the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then, the pH is adjusted to 11 by addition of sodium hydroxide and thesolution is heated to 50° C. and kept for 30 minutes at 50° C. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 70 minutes. Aftercooling the solution to room temperature the pH is adjusted to 6-7 bythe addition of sodium hydroxide.

The solution is then filtered through a sterilization filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85 and then dried in vacuumat 50° C.

The yield is 171 g (corresponding to 86% of the theoretical value) of abrown amorphic powder having an iron content of 21.35% weight/weight(measured complexometrically),

Molecular weight mw 170 kDa.

Comparative Test

In the following, the characteristics of the iron carbohydrate complexesare compared with a commercially available iron sucrose complex. It canbe seen that the iron content can be enhanced, the thermal treatment canbe carried out at higher temperatures and the toxicity (LD₅₀) can belowered in accordance with the invention.

According to Iron the invention hydroxide/sucrose Fe content [%] 5.0 2.0pH 5-7 10.5-11.0 mw [kDa]¹  80-350 34-54 Thermal treatment 121° C./15′100° C./35′ LD₅₀ i.v., w.m. [mg >2000 >200 Fe/kg body weight]

1-11. (canceled)
 12. An iron (III) carbohydrate complex comprising anoxidized maltodextrin and the average molecular weight of the iron (III)carbohydrate complex is 80 kDa to 400 kDa.
 13. The iron (III)carbohydrate complex of claim 12, wherein 80% to 100% of aldehyde groupsin the oxidized maltodextrin are oxidized.
 14. The iron (III)carbohydrate complex of claim 12, wherein the reducing power of terminalglucose groups of the oxidized maltodextrin is lowered to 20% or lessrelative to a non-oxidized maltodextrin.
 15. The iron (III) carbohydratecomplex of claim 12, wherein oxidation has occurred predominately at theterminal aldehyde group of the maltodextrin.
 16. The iron (III)carbohydrate complex of claim 12, wherein the oxidized maltodextrin isobtained by oxidation of maltodextrin in an aqueous hypochloritesolution.
 17. The iron (III) carbohydrate complex of claim 12 suitablefor administration as therapy or prophylaxis for an iron deficiencycondition.
 18. The iron (III) carbohydrate complex of claim 12 suitablefor parenteral administration as a medicament to an animal in needthereof.
 19. The iron (III) carbohydrate complex of claim 12 suitablefor parenteral administration as a medicament to an animal in needthereof in the form of a single dose of 500 mg to 1000 mg iron.
 20. Theiron (III) carbohydrate complex of claim 12 in the form of a powder. 21.An aqueous solution of the iron (III) carbohydrate complex of claim 12.22. The aqueous solution of the iron (III) carbohydrate complex of claim21 suitable for intravenous administration as a medicament to an animalin need thereof.
 23. The aqueous solution of the iron (III) carbohydratecomplex of claim 21 having an iron content of 1% weight/volume of thesolution to 20% weight/volume of the solution.
 24. The aqueous solutionof the iron (III) carbohydrate complex of claim 22 having an ironcontent of 1% weight/volume of the solution to 20% weight/volume of thesolution.
 25. The aqueous solution of the iron (III) carbohydratecomplex of claim 21 that has been sterilized at a temperature of atleast 121° C.
 26. The aqueous solution of the iron (III) carbohydratecomplex of claim 23 that has been sterilized at a temperature of atleast 121° C.
 27. The aqueous solution of the iron (III) carbohydratecomplex of claim 24 that has been sterilized at a temperature of atleast 121° C.
 28. The aqueous solution of the iron (III) carbohydratecomplex of claim 21 that is substantially free of preservatives.
 29. Theaqueous solution of the iron (III) carbohydrate complex of claim 23 thatis substantially free of preservatives.
 30. The aqueous solution of theiron (III) carbohydrate complex of claim 24 that is substantially freeof preservatives.
 31. The aqueous solution of the iron (III)carbohydrate complex of claim 27 that is substantially free ofpreservatives.
 32. An iron (III) carbohydrate complex comprising anoxidized maltodextrin and the average molecular weight of the iron (III)carbohydrate complex is 118 kDa to 400 kDa.
 33. The iron (III)carbohydrate complex of claim 32, wherein 80% to 100% of aldehyde groupsin the oxidized maltodextrin are oxidized.
 34. The iron (III)carbohydrate complex of claim 32, wherein reactivity caused by theglucose content of the oxidized maltodextrin is 20% or less.
 35. Theiron (III) carbohydrate complex of claim 32, wherein oxidation hasoccurred predominately at the terminal aldehyde group of themaltodextrin.
 36. The iron (III) carbohydrate complex of claim 32,wherein the oxidized maltodextrin is obtained by oxidation ofmaltodextrin in an aqueous hypochlorite solution.
 37. The iron (III)carbohydrate complex of claim 32 suitable for administration as therapyor prophylaxis for an iron deficiency condition.
 38. The iron (III)carbohydrate complex of claim 32 suitable for parenteral administrationas a medicament to an animal in need thereof.
 39. The iron (III)carbohydrate complex of claim 32 suitable for parenteral administrationas a medicament to an animal in need thereof in the form of a singledose of 500 mg to 1000 mg iron.
 40. The iron (III) carbohydrate complexof claim 32 in the form of a powder.
 41. An aqueous solution of the iron(III) carbohydrate complex of claim
 32. 42. The aqueous solution of theiron (III) carbohydrate complex of claim 41 suitable for intravenousadministration as a medicament to an animal in need thereof.
 43. Theaqueous solution of the iron (III) carbohydrate complex of claim 41having an iron content of 1% weight/volume of the solution to 20%weight/volume of the solution.
 44. The aqueous solution of the iron(III) carbohydrate complex of claim 42 having an iron content of 1%weight/volume of the solution to 20% weight/volume of the solution. 45.The aqueous solution of the iron (III) carbohydrate complex of claim 41that has been sterilized at a temperature of at least 121° C.
 46. Theaqueous solution of the iron (III) carbohydrate complex of claim 43 thathas been sterilized at a temperature of at least 121° C.
 47. The aqueoussolution of the iron (III) carbohydrate complex of claim 44 that hasbeen sterilized at a temperature of at least 121° C.
 48. The aqueoussolution of the iron (III) carbohydrate complex of claim 41 that issubstantially free of preservatives.
 49. The aqueous solution of theiron (III) carbohydrate complex of claim 43 that is substantially freeof preservatives.
 50. The aqueous solution of the iron (III)carbohydrate complex of claim 44 that is substantially free ofpreservatives.
 51. The aqueous solution of the iron (III) carbohydratecomplex of claim 47 that is substantially free of preservatives.